Proteomics

Dataset Information

0

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation


ABSTRACT: Filamin C is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familiar and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from filamin C and abolishes the dimerization property of Ig-like domain 24. We previously characterized "knock-in" mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: (i) the expression level of filamin C protein is drastically reduced; (ii) mutant filamin C is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack BAG3; (iv) the expression of HSPB7 is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective filamin C dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that filamin C is important for mechanosensing in the context of Z‑disc stabilization and maintenance.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus musculus  

TISSUE(S): Skeletal Muscle Fiber

DISEASE(S): Myofibrillar Myopathy

SUBMITTER: Britta Eggers  

LAB HEAD: Prof. Dr. Katrin Marcus

PROVIDER: PXD020097 | Pride | 2020-09-09

REPOSITORIES: pride

altmetric image

Publications

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation.

Schuld Julia J   Orfanos Zacharias Z   Chevessier Frédéric F   Eggers Britta B   Heil Lorena L   Uszkoreit Julian J   Unger Andreas A   Kirfel Gregor G   van der Ven Peter F M PFM   Marcus Katrin K   Linke Wolfgang A WA   Clemen Christoph S CS   Schröder Rolf R   Fürst Dieter O DO  

Acta neuropathologica communications 20200904 1


Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-lik  ...[more]

Similar Datasets

2020-07-24 | PXD016657 | Pride
2022-06-06 | PXD008875 | Pride
2015-07-13 | E-GEOD-70819 | ArrayExpress
2014-10-02 | E-GEOD-61952 | ArrayExpress
2011-10-13 | GSE32915 | GEO
| GSE61952 | GEO
2010-08-25 | GSE23762 | GEO
2015-11-19 | E-GEOD-75127 | ArrayExpress
2019-05-14 | E-GEOD-70819 | ExpressionAtlas
| GSE103475 | GEO